The objectives of this proposal are to define the molecular mechanisms of antibiotic interactions with mammalian cells. These studies will enhance understanding of adverse drug reactions associated with aminoglycosides and chloramphenicol and may provide a basis for specific pharmacologic manipulation of immune responses. Aminoglycoside accumulation will be studied in the kidney, cultured renal tubular epithelial cells, and micropuncture samples of endolymph, and the pathogenesis of nephro- and oto-toxicity of these drugs will be described using morphological, functional and biochemical techniques. Chloramphenicol-induced inhibition of NADH oxidase will be evaluated as a possible mechanism for the gray syndrome and therapy explored. Stereoisomers, analogues and metabolites of chloramphenicol will be examined for reversible and irreversible effects on lympho-hematopoietic tissues using experimental animals and in vitro models. Evidence that the antiproliferative effects of chloramphenicol are unrelated to altered mitochondrial protein synthesis will be extended. Possible suppression of lymphokine production in mature effector lymphocytes by niridazole and rifampicin will be examined.